The long term objective of this Program Project is to develop protegrins as a safe and effective chemoprotective barrier to protect women from the acquisition of HIV, gonorrhea, chlamydia, syphilis, herpes or trichomonas infection during sexual intercourse. protegrins are recently discovered natural peptide antibiotics that were originally isolated from porcine leukocytes. The contain 16-18 amino acids, including 4 cysteine residues that form 2 intramolecular disulfide bonds. Unlike defensins, to which they show primary sequence homology, and many other antibiotic peptides of animal origin, the antimicrobial activity of protegrins is enhanced by the presence of physiological salt concentrations and serum. The relatively simple structure of protegrins makes them highly amenable to solid phase chemical synthesis, and synthetic and native protegrins show identical antimicrobial activity in vitro. Protegrins rapidly inactivated HIV, C. trachomatis, N. gonorrhoeae and T. pallidum in vitro when added in micromolar concentrations, typically 5 mug/ml or below. Somewhat higher concentrations of protegrins also inactivated herpes simplex type II and Trichomonas vaginalis. Despite their unusually broad antimicrobial spectrum, protegrins were not cytotoxic towards mammalian fibroblasts, lymphocytes or macrophages, even when tested at concentrations of 50 mug/ml. The specific aims of the overall program project include designing protegrin congeners with enhanced efficacy against STD organisms (which will also allow us to examine the structure-function relationships of protegrins), testing the protegrin congeners against laboratory and clinical isolates of these organisms, and ascertaining the ability of topical protegrins to protect the lower genital tracts of female mice from infection by C. trachomatis. This Program Project Grant combines the talents and experiences of a consortium of leading STD scientists in an integrated and interactive program to develop a novel, female-controlled modality to prevent STD.